Abstract

The role of CD28 homologue CTLA4 in T cell activation has been obscure and controversial. Recent findings suggest that it plays a critical role in down regulation of T cell responses. The mechanism of this down-regulation is not known. The overall aim of this project is to test the hypothesis that the outcome of T cell stimulation is regulated by a complex and dynamic integration of antigen specific signals from the TCR, co-stimulatory signals from CD28 and attenuating signals from CTLA4. One implication of this hypothesis is that CTLA4 may play an important role in peripheral self tolerance and another is that CTLA4 might serve as a target for the manipulation of immune responses.
The specific aims art 1) to examine the role of CTLA4 in regulation of early stages of T cell activation; 2) to examine the CTLA4 role in later stages of T cell responses; 3) to determine the basis for the lympho-proliferative disorder that occurs in CTLA4 KO mice; 4) to determine the effectiveness of CTLA4 blockade as a vaccine strategy.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA040041-18
Application #
6375726
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Mccarthy, Susan A
Project Start
1985-01-01
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2003-03-31
Support Year
18
Fiscal Year
2001
Total Cost
$242,056
Indirect Cost

  Institution

Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Berkeley
State
CA
Country
United States
Zip Code
94704

  Publications

Kreymborg, Katharina; Haak, Stefan; Murali, Rajmohan et al. (2015) Ablation of B7-H3 but Not B7-H4 Results in Highly Increased Tumor Burden in a Murine Model of Spontaneous Prostate Cancer. Cancer Immunol Res 3:849-54
Corse, Emily; Gottschalk, Rachel A; Park, Joon Seok et al. (2013) Cutting edge: chronic inflammatory liver disease in mice expressing a CD28-specific ligand. J Immunol 190:526-30
Krummel, Matthew F; Allison, James P (2011) Pillars article: CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. The journal of experimental medicine. 1995. 182: 459-465. J Immunol 187:3459-65
Wei, Joyce; Loke, P'ng; Zang, Xingxing et al. (2011) Tissue-specific expression of B7x protects from CD4 T cell-mediated autoimmunity. J Exp Med 208:1683-94
Corse, Emily; Gottschalk, Rachel A; Krogsgaard, Michelle et al. (2010) Attenuated T cell responses to a high-potency ligand in vivo. PLoS Biol 8:
Thompson, R Houston; Zang, Xingxing; Lohse, Christine M et al. (2008) Serum-soluble B7x is elevated in renal cell carcinoma patients and is associated with advanced stage. Cancer Res 68:6054-8
Pentcheva-Hoang, Tsvetelina; Chen, Lieping; Pardoll, Drew M et al. (2007) Programmed death-1 concentration at the immunological synapse is determined by ligand affinity and availability. Proc Natl Acad Sci U S A 104:17765-70
Zang, Xingxing; Loke, P'ng; Kim, Jayon et al. (2006) A genetic library screen for signaling proteins that interact with phosphorylated T cell costimulatory receptors. Genomics 88:841-5
Pentcheva-Hoang, Tsvetelina; Egen, Jackson G; Wojnoonski, Kathleen et al. (2004) B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse. Immunity 21:401-13
Stohl, William; Xu, Dong; Kim, Kyoung Soo et al. (2004) MHC class II-independent and -dependent T cell expansion and B cell hyperactivity in vivo in mice deficient in CD152 (CTLA-4). Int Immunol 16:895-904

Showing the most recent 10 out of 57 publications